The present invention is related generally to the therapy of lower respiratory tract diseases caused by respiratory viruses or other infectious agents. More particularly, the present invention is related to a novel, effective, and rapid method of treating lower respiratory tract disease caused particularly by parainfluenza virus type 3 (PIV3) or adenovirus type 5 (Ad-5) by direct administration of corticosteroids or anti-inflammatory drugs into the lower respiratory tract. One embodiment of the invention is primarily directed to a method of treating lower respiratory tract infections that alters the immune response to infection, and is not concerned with the presence of viable infectious agents per se. However, the method of the present invention can also be used in combination with anti-infective therapy.
Another embodiment of the invention includes anti-infective therapy. This embodiment is directed to a method of treating lower respiratory tract disease caused particularly by respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) by administering a combination of an anti-infectious agent and an anti-inflammatory agent. Therapy using a topically applied combination of an anti-infectious agent plus an anti-inflammatory agent dramatically reduces both components of pulmonary pathology, namely alveolar inflammation (interstitial pneumonia) and bronchiolar inflammation (bronchiolitis), and accelerates clearance of the infectious agent.
Lower respiratory tract disease caused by viruses and other infectious agents is a serious problem in all ages, particularly in the very young and the elderly. Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are the leading causes of pulmonary disease in infants and children worldwide (Chanock, 1990, in Fields et al., eds., Virology, 2d ed., New York, Raven Press, pp. 963-988; McIntosh, 1990, in Fields et al., eds., Virology. 2d ed., New York, Raven Press, pp. 1045-1072). While the clinical and financial burdens of the two viruses are uncertain, a 1985 study by the National Academy of Sciences estimated that nearly 10,000 deaths and medical costs in excess of one billion dollars are due to RSV and PIV3 each year in the United States (New Vaccine Development. Establishing Priorities. Vol. 1. Diseases of Importance in the United States, Washington, D.C., National Academy Press, 1985, pp. 385-409). Clinical and financial burdens in other countries are assumed to be at least as great as in this country, although no estimates have been published. In spite of their importance, however, no vaccine has been developed against either virus.
Currently there is no licensed therapy for PIV3 or Ad-5 lower respiratory disease and the licensed therapy for treating diseases caused by other respiratory viruses is of limited efficacy. In the case of respiratory syncytial virus (RSV), treatment requires the delivery of ribavirin (1-beta-D-ribofuranosyl-1,2,4,-triazole-3-carboxamide) by small particle aerosol for 12-20 hours a day for at least 3 days (Hall et al., 1983 New Eng. J. Med. 308:1443-1447; Taber et al., 1983 Pediatrics 72:613-618). This treatment involves intervention in the replicative cycle of the RSV. Ribavirin appears to be of only marginal efficacy, and its use has recently come under increasing criticism (Khan, 1991 Am. Rev. Resp. Dis. 143:A510).
Inhaled corticosteroids (e.g., beclamethasone) are commonly used in the treatment of allergic asthma (reactive airway disease). However, corticosteroid therapy was not found to be beneficial in the treatment of viral bronchiolitis, especially that caused by RSV (Leer et al., 1969 Amer. J. Dis. Child. 117:495). Indeed, the prevailing wisdom is that the use of corticosteroids (and presumably other anti-inflammatory agents) during respiratory viral infections is contraindicated (Stecenko, 1987, Contemp. Pediat. 4:121; Thomas et al., 1984, Arch Virol. 79:67-77; Sieber, 1977, Pediat. Res. 11:230; Mandell, Douglas & Bennett, Principles and Practice of Infectious Diseases, Third Edition, 1990, p. 1274). It should be noted, however, that all of these reports were based upon the use of systemically administered corticosteroids. The use of topically administered corticosteroids, or other anti-inflammatory agents such as ibuprofen or indomethacin, in the treatment of infectious respiratory tract disease has not been addressed in the scientific literature.
Recent reports show that the major component of pulmonary disease caused by PIV3 and Ad-5 is the host immunologic response to infection, rather than direct viral injury to host tissues (Porter et al., 1991 J. Virol. 65:103-111; Ginsberg et al., 1991 Proc. Nat. Acad. Sci. USA 88:1651-1655). Therefore, elimination of virus from infected tissues, such as in case of ribavirin therapy, may not be expected to reverse host responses already triggered by infection. The host immunologic response is also triggered by many bacterial, fungal and parasitic pulmonary infections, as exemplified by Mycoplasma pneumoniae or Pneumocystis carinii pneumonias.
The use of anti-inflammatory agents, particularly corticosteroids, in infectious diseases has long been controversial (McGowan, 1992, ,J. Infect. Dis. 165:1-3), presumably due to the fact that suppression of the inflammatory response can lead to impairment of the host's ability to clear the infectious agent. However, three sets of observations have recently called into question the conventional wisdom. First, high doses of systemically administered corticosteroids may have a lifesaving effect in viral meningitis (McGowan, 1992 ,J. Infect. Dis. 165:1-3). Second, it has become evident that the use of high doses of corticosteroids, in conjunction with chemotherapeutic agents, has lifesaving potential in many cases of Pneumocystis carinii pneumonia in HIV patients (Rahal, 1991 ,New Eng. J. Med. 324:1666). Finally, it has become apparent that at least three major respiratory viruses (RSV, PIV3, and type 5 adenovirus), which cause minimal direct viral lysis of host tissues, produce a pulmonary disease which is predominantly host-mediated. That is, most, if not all, of the pulmonary pathology is due to the accumulation of host inflammatory and immune cells in lung tissues, rather than the direct destruction of host tissue by the viruses (Ginsberg, 1989 Proc. Nat. Acad. Sci. USA 86:3823-3827; Ginsberg, 1990 Proc. Nat. Acad. Sci. USA 87:6191-6195; Porter, 1991 Am. J. Pathol. 93:185-205; Prince, 1978 J. Virol. 65:103-111).
Of direct relevance to the current proposal are observations from the mouse model of type-5 adenovirus pneumonia that cytokine levels (tumor necrosis factor, interleukin-1, and interleukin-6) correlate with pulmonary pathology (Ginsberg, 1991 Proc. Nat. Acad. Sci. USA 88:1651-1655). Suppression of these cytokines with specific antiserum causes partial ablation of the pathologic process. Corticosteroid treatment of mice prior to viral challenge results in suppression of all three of these cytokines and nearly complete prevention of pneumonia.
The theoretical basis of the proposed combination of anti-infective and anti-inflammatory therapy is the assumption that antiviral therapy, alone, would be unlikely to have a dramatic effect on a pulmonary disease process caused primarily by the host inflammatory response. Indeed, the demonstration in experimental models, both of RSV and PIV3, that pulmonary pathology reaches its maximum two days after peak viral titers (Porter, 1991 J. Virol. 65:103-111,; Prince, 1978 Am. J. Pathol. 93:185-205,) suggests that viral titers may already be declining when patients are hospitalized with RSV or PIV3 pneumonia. Since there is no drug currently identified with both antiviral (RSV and PIV3) and anti-inflammatory properties, a combination of a potent antiviral (human immunoglobulin, IgG) and a potent anti-inflammatory (corticosteroid) was used.
Two viruses were chosen for the anti-infective therapy, parainfluenza virus type 3 (PIV3) and respiratory syncytial virus (RSV). These viruses were chosen for the following reasons: (1) RSV is the most important cause of infectious pneumonia in infants, and PIV3 is the next most important cause; and (2) antiviral therapies have been demonstrated against both viruses. In the case of RSV, ribavirin has been licensed for topical therapy and is in widespread clinical use; additionally, purified antibody with high levels of anti-RSV activity has been shown effective in eliminating pulmonary RSV when used topically (Prince et al., 1987 J. Virol. 61:1851-1854; Prince et al., U.S. Pat. No. 4,800,078).
The examples and discussion provided in this application demonstrate that (1) combined topical therapy using an anti-infective agent and a corticosteroid dramatically reduces pulmonary pathology caused by each of the two viruses, RSV and PIV3; and (2) corticosteroids are effective when used either with an antiviral chemotherapeutic agent such as ribavirin or an antiviral biologic agent such as purified antibody.
The invention provides an effective method of treating lower respiratory tract disease which targets the injurious immunologic host response. As discussed above, the use of anti-inflammatory agents to treat infections is usually not recommended because the inflammatory response is part of the immune system, and one would not expect suppressing part of the immune system to be of benefit in treating an infection. This invention unexpectedly provides a method of treating lower respiratory tract disease which uses anti-inflammatory agents to reduce the host's immune response to the disease.
Applicants' studies have shown that a therapeutic approach combining topically administered antiviral and anti-inflammatory agents accelerates the clearance of virus from infected laboratory animals, while reversing the disease process in their lungs. These studies have employed human immunoglobulin (IgG) as the antiviral agent, and triamcinolone acetonide as the anti-inflammatory agent; however, other antiviral and anti-inflammatory agents may also be used. IgG and corticosteroids are already in common clinical use for other indications and are relatively inexpensive. Clinical trials have not been performed. However, based on the dramatic results of the combined anti-infective and anti-inflammatory therapy, the invention should provide a dramatic, yet inexpensive, treatment of the most common forms of infant and childhood pulmonary disease.